Review: Mechanisms of How the Intestinal Microbiota Alters the Effects of Drugs and Bile Acids

Abstract

Information on the intestinal microbiota has increased exponentially this century because of technical advancements in genomics and metabolomics. Although information on the synthesis of bile acids by the liver and their transformation to secondary bile acids by the intestinal microbiota was the first example of the importance of the intestinal microbiota in biotransforming chemicals, this review will discuss numerous examples of the mechanisms by which the intestinal microbiota alters the pharmacology and toxicology of drugs and other chemicals. More specifically, the altered pharmacology and toxicology of salicylazosulfapridine, digoxin, l-dopa, acetaminophen, caffeic acid, phosphatidyl choline, carnitine, sorivudine, irinotecan, nonsteroidal anti-inflammatory drugs, heterocyclic amines, melamine, nitrazepam, and lovastatin will be reviewed. In addition, recent data that the intestinal microbiota alters drug metabolism of the host, especially Cyp3a, as well as the significance and potential mechanisms of this phenomenon are summarized. The review will conclude with an update of bile acid research, emphasizing the bile acid receptors (FXR and TGR5) that regulate not only bile acid synthesis and transport but also energy metabolism. Recent data indicate that by altering the intestinal microbiota, either by diet or drugs, one may be able to minimize the adverse effects of the Western diet by altering the composition of bile acids in the intestine that are agonists or antagonists of FXR and TGR5. Therefore, it may be possible to consider the intestinal microbiota as another drug target.

Fig. 1.

Metabolism of salicylazosulfapyridine.

Fig. 2.

Metabolism of digoxin.

Fig. 3.

Metabolism of l-dopa.

Fig. 4.

Sulfation of acetaminophen and cresol.

Fig. 5.

Metabolism of caffeic acid

Fig. 6.

Metabolism of phosphatidylcholine.

Fig. 7.

Chemical structures of choline and carnitine.

Fig. 8.

Metabolism of Sorivudine.

Fig. 9.

Metabolism of irinotecan.

Fig. 10.

Metabolism of diclofenac.

Fig. 11.

Chemical structures of PhIP and IQ.

Fig. 12.

Chemical structures of melamine and cyanuric acid.

Fig. 13.

Metabolism of nitrazepam.

Fig. 14.

Metabolism of lovastatin.

Fig. 15.

Messenger RNA of Cyp3a11 and Cyp4a14 in conventional and germ-free mice.

Fig. 16.

Metabolism of tryptophan.

Fig. 17.

Synthesis and metabolism of bile acids.

Fig. 18.

Chemical structures of bile acids.

Fig. 18.

Chemical structures of bile acids.

Fig. 19.

Uptake and efflux transporters of bile acids.

Fig. 20.

Schematic diagram of (I) FXR receptor in liver, (II) FXR receptor in intestine, (IIIA) TGR5 receptor in intestine, (IIIB) TGR5 receptor in gallbladder, and (IIIC) TGR5 receptor in fat and muscle.